Degenerative cartilagenous disorders broadly describe a collection of diseases characterized by degeneration or metabolic abnormalities of the connective tissues that are manifested by pain, stiffness and limitation of motion of the affected body parts. The origin of these disorders can be pathological or as a result of trauma or injury.
Osteoarthritis (OA), also known as osteoarthrosis or degenerative joint disease, is the result of a series of localized degenerative processes that affect the articular structure and result in pain and diminished function. The incidence of OA increases with age, and evidence of OA involvement can be detected in some joints in the majority of the population by age 65. OA is often also accompanied by a local inflammatory component that may accelerate joint destruction.
OA is characterized by disruption of the smooth articulating surface of cartilage, followed by formation of clefts and fibrillation, and ultimately by the full-thickness loss of the cartilage. Coincident with the cartilaginous changes are alterations of the periarticular bone. These include the development of palpable bone enlargements at the joint margins and deformity resulting from assymetric cartilage destruction. OA symptoms include local pain at the affected joints, especially after use. With disease progression, symptoms may develop into a continuous aching sensation, local discomfort, and cosmetic alterations of the affected joint.
In contrast to the localized disorder OA, rheumatoid arthritis (RA) is a systematic destructive and debilitating disease that is believed to begin in the synovium, the tissues surrounding the joint. The prevalence of RA is about ⅙ that of OA in the general population of the United States. It is a chronic autoimmune disorder characterized by symmetrical synovitis of the joint and typically affects small and large diarthrodial joints, leading to their progressive destruction. As the disease progresses, the symptoms of RA may also include fever, weight loss, thinning of the skin, multi-organ involvement, scleritis, corneal ulcers, the formation of subcutaneous or subperiosteal nodules, and premature death.
The response of normal patients (e.g., preinjury or predisease) to injury or arthritic degeneration is often sub-optimal. The biochemical and mechanical properties of this damaged cartilage differ from those of normal cartilage, resulting in inadequate or altered function. This damaged cartilage, termed herein “fibrocartilage,” does not approximate the durability and function of normal cartilage.
Since cartilage is avascular and mature chondrocytes have little intrinsic potential for replication, mature cartilage has limited ability for repair. Thus, damage to the cartilage layer that does not penetrate to the subchondral bone does not undergo efficient repair. In contrast, when the subchondral bone is penetrated, its vascular supply allows a triphasic repair to take place. The resulting tissue is usually mechanically sub-optimal fibrocartilage.
The degradation associated with osteoarthritis usually initially appears as fraying and fibrillation of the surface. Loss of proteoglycan from the matrix also occurs. As the surface fibrillation progresses, the defects penetrate deeper into the cartilage, resulting in loss of cartilage cells and matrix. The subchondral bone thickens, is slowly exposed, and may appear polished. Bony nodules or osteophytes also often form at the periphery of the cartilage surface and occasionally grow over the adjacent eroded areas. If the surface of these bony outgrowths is permeated, vascular outgrowth may occur and cause the formation of tissue plugs containing fibrocartilage.
The transplantation of chondrocytes is known as a means of stimulating cartilage repair. However, the possibility of the host's immunogenic response as well as the possible transmission of viral and other infectious diseases makes this method less desirable. These risks can be minimized to some extent with allograft and autogenous transplants; however, the culturing and growth of patient-specific cells is cost prohibitive on a mass scale.
Other methods of stimulating cartilage repair include the antagonism of molecules that are associated with or aggravate cartilage destruction, for example, interleukin-1-alpha (IL-1∀) and nitric oxide (NO). The cytokine IL-1∀ has catabolic effects on cartilage, including the generation of synovial inflammation and up-regulation of matrix metalloproteinases and prostaglandin expression (Baragi et al., J. Clin. Invest., 96: 2454-2460 (1995); Baragi et al., Osteoarthritis Cartilage, 5: 275-282 (1997); Evans et al., J. Leukoc. Biol., 64: 55-61 (1998); Evans and Robbins, J. Rheumatol., 24: 2061-2063 (1997); Kang et al., Biochem. Soc. Trans., 25: 533-537 (1997); Kang et al., Osteoarthritis Cartilage, 5: 139-143 (1997)). One means of antagonizing IL-1∀ is through application of soluble IL-1 receptor antagonist (IL-1ra), a naturally-occurring protein that inhibits the effects of IL-1 by preventing IL-1 from binding to and activating its receptor on chondrocytes and synoviocytes, thereby lowering the effective concentration of IL-1.
Nitric oxide (NO) plays a substantial role in the destruction of cartilage (Amin et al., Curr. Opin. Rheum., 10: 263-268 (1998)). Cartilage obtained from osteoarthritic joints endogenously produces large amounts of NO. Normal cartilage does not produce NO unless stimulated with cytokines such as IL-1, while osteoarthritic cartilage explants continue to express NO synthase for up to 3 days in culture despite the absence of added stimuli. Moreover, the inhibition of NO has been shown to prevent IL-1∀-mediated cartilage destruction and chondrocyte death as well as the progression of osteoarthritis.
The ability of peptide growth factors to promote repair of damaged cartilage has also been examined. Peptide growth factors are very significant regulators of cartilage growth and cell behavior (i.e., differentiation; migration, division, or matrix synthesis and/or breakdown) (Chen et al., Am J. Orthop., 26: 396-406 (1997)). These factors are under investigation for their potential to induce host cartilage repair without transplantation of cells, and are being incorporated into engineered devices for implantation.
Because growth factors are soluble proteins of relatively small molecular mass that are rapidly absorbed and/or degraded, a great challenge exists in making them available to cells in sufficient quantity and for sufficient duration. It is likely desirable to have different factors present at the repair site during different parts of the developmental cycle, and for varying lengths of time. The ideal delivery vehicle is biocompatible and resorbable, has the appropriate mechanical properties, and results in no harmful degradation products. Growth factors that previously have been proposed to stimulate cartilage repair include insulin-like growth factor-I (IGF-1) (Osborn, J. Orthop. Res., 7: 35-42 (1989); Florini and Roberts, J. Gerontol., 35: 23-30 (1980); U.S. Pat. No. 5,843,899), basic fibroblast growth factor (bFGF), [Toolan et al., J. Biomec. Mat. Res., 41: 244-50 (1998); Sah et al., Arch. Biochem. Biophys., 308: 137-47 (1994)), bone morphogenetic protein (BMP) (Sato and Urist, Clin. Orthop. Relat. Res., 183: 180-187 (1984); Chin et al., Arthritis Rheum. 34: 314-324 (1991)), and transforming growth factor beta (TGF-∃) (Hill and Logan, Prog. Growth Fac. Res., 4: 45-68 (1992); Guerne et al., J. Cell Physiol., 158: 476-484 (1994); Van der Kraan et al., Ann. Rheum. Dis., 51: 643-647 (1992)).
It has been well established that the GH/IGF/IGFBP system is involved in the regulation of anabolic and metabolic homeostasis and that defects in this system may adversely affect growth, physiology, and glycemic control (Jones et al., Endocr. Rev., 16: 3-34 (1995); Davidson, Endocr. Rev., 8: 115-131 (1987); Moses, Curr. Opin. Endo. Diab., 4: 16-25 (1997)). It has been proposed that IGF-1 could be useful for the treatment or prevention of osteoarthritis, because of its ability to stimulate both matrix synthesis and cell proliferation in culture (Osborn, J. Orthop. Res., 7: 35-42 (1989)). IGF-1 has been administered with sodium pentosan polysulfate (PPS) (a chondrocyte catabolic activity inhibitor) to severely osteoarthritic canines with the effect of reducing the severity of the disease perhaps by lowering the levels of active neutral metalloproteinase in the cartilage. In the model of mildly osteoarthritic canines, therapeutic intervention with IGF-1 and PPS together appeared to successfully maintain cartilage structure and biochemistry, while IGF alone was ineffective, as described in Rogachefsky, Osteoarthritis and Cartilage, 1: 105-114 (1993); Rogachefsky et al., Ann. NY Acad. Sci., 732: 392-394 (1994). The use of IGF-1 either alone or as an adjuvant with other growth factors to stimulate cartilage regeneration has been described in WO 91/19510, WO 92/13565, U.S. Pat. No. 5,444,047, and EP 434,652.
IGF-1 has also been found useful in the treatment of osteoporosis in mammals exhibiting decreased bone mineral density and those exposed to drugs or environmental conditions that result in bone density reduction and potentially osteoporosis, as described in EP 560,723 and EP 436,469.
IGF-1 insufficiency may have an etiologic role in the development of osteoarthritis (Coutts et al., “Effect of growth factors on cartilage repair,” Instructional Course Lect., 47: 487-494 (Amer. Acad. Orthop. Surg.: Rosemont, Ill. 1997)). Some studies indicate that serum IGF-1 concentrations are lower in osteoarthritic patients than control groups, while other studies have found no difference. Nevertheless, it has been shown that both serum IGF-1 levels and chondrocyte responsiveness to IGF-1 decrease with age, with the latter likely due to high levels of IGF binding proteins (IGFBPs) (Florini and Roberts, J. Gerontol., 35: 23-30 (1980); Martin et al., J. Orthop. Res., 15: 491-498 (1997); Fernihough et al., Arthr. Rheum. 39: 1556-1565 (1996)). Thus, both the decreased availability of IGF-1 as well as diminished chondrocyte responsiveness/disregulation of IGFBPs thereto may contribute to the impaired cartilage matrix homeostasis and tissue degeneration that occurs with advancing age and disease.
Of the IGFBPs, IGFBP-3 appears to be the most responsible for regulating the total levels of IGF-1 and IGF-2 in plasma. IGFBP-3 is a GH-dependent protein and is reduced in cases of GH-deficiency or resistance (Jones et al., supra; Rosenfield et al., “IGF-1 treatment of syndromes of growth hormone insensitivity” In: The insulin-like growth factors and their regulatory proteins, Eds Baxter R C, Gluckman P D, Rosenfield R G. Excerpta Medica, Amsterdam, 1994), pp 457-464; Scharf et al., J. Hepatology, 25: 689-699 (1996)). IGFBPs are able to enhance or inhibit IGF activity, depending largely on their post-translational modifications and tissue localization (reviewed in Jones and Clemmons, Endocr. Rev. 16:3-34 (1995); Collett-Solberg and Cohen, Endocrinol. Metabol. Clin. North Am. 25:591-614 (1996)). In addition, disregulation in IGFBPs (-3, -4 and/or -5) may play a key role in arthritic disorders (Chevalier and Tyler, Brit. J. Rheum. 35: 515-522 (1996); Olney et al., J. Clin. Endocrinol. Metab. 81: 1096-1103 (1996); Martel-Pelletier et al., Inflamm. Res., 47: 90-100 (1998)). It has been reported that IGF-1 analogs with very low binding affinity for IGFBPs were more effective than wild-type IGF-1 in stimulating proteoglycan synthesis (Morales, Arch Biochem. Biophys. 343(2), 164-172 (1997)). More recent data, however, suggest that IGFBPs contribute to IGF binding to and transport through cartilage tissue, and IGFBPs may thus regulate bioavailability of IGF-1 within the joint (Bhakta et al., J. Biol. Chem., 275: 5860-5866 (2000)).
The biodistribution of IGF-1 critically depends on (a) the formation of long-lived high molecular weight complexes and (b) the absolute IGFBP concentrations. The majority of IGF-1 in the circulation is found in complex with IGFBP-3 and a third protein termed acid-labile subunit (ALS) (Bach and Rechler, Diabetes Reviews, 3: 38-61 (1995); Clemmons, Cytokine Growth Factor Rev., 8: 45-62 (1997); Jones and Clemmons, Endocr. Rev., 16: 3-34 (1995)). This ternary complex of 150-kD molecular weight is unable to traverse the vasculature walls and acts as a circulating reservoir for IGF's. As a consequence, the serum half-life of IGF-1 in ternary complexes is reported to be 12-15 hours, as opposed to 30 minutes in binary complexes, or 10 minutes in the free form (Simpson et al., Growth Horm IGF Res, 8: 83-95 (1998); Twigg and Baxter, J. Biol. Chem., 273: 6074-6079 (1998)).
IGFBP-3 and -5 are apparently unique in their ability to form a ternary complex with ALS. ALS association occurs only in the presence of IGF-1, and a basic motif in the carboxy-terminal domains of IGFBP-3 and -5 seems to mediate this interaction (Baxter et al., J. Biol. Chem., 267: 60-65 (1992); Firth et al., J. Biol. Chem., 273: 2631-2638 (1998); Twigg and Baxter, supra).
The second determinant of IGF-1 biodistribution is the total concentration of binding proteins: IGFBP-3 is the most abundant binding protein, followed by IGFBP-1 and -2 levels, whereas the serum concentrations of IGFBP-4, -5, and -6 are quite low (Clemmons, Cytokine Growth Factor Rev., 8: 45-62 (1997)). IGFBP-3 therefore represents the main IGF-1 carrier in the blood. In contrast, a substantial portion of IGFBP-1 and -2 in the blood are unoccupied. Hence, they appear to be the major modulators of free IGF-1 levels (Clemmons, 1997, supra).
WO 94/04569 discloses a specific binding molecule, other than a natural IGFBP, that is capable of binding to IGF-1 and can enhance the biological activity of IGF-1. WO 98/45427 published Oct. 15, 1998; Lowman et al., Biochemistry, 37: 8870-8878 (1998); and Dubaquié and Lowman, Biochemistry, 38: 6386 (1999) disclose IGF-1 agonists identified by phage display. Also, WO 97/39032 discloses ligand inhibitors of IGFBP's and methods for their use. Further, U.S. Pat. No. 5,891,722 discloses antibodies having binding affinity for free IGFBP-1 and devices and methods for detecting free IGFBP-1 and a rupture in a fetal membrane based on the presence of amniotic fluid in a vaginal secretion, as indicated by the presence of free IGFBP-1 in the vaginal secretion. WO 00/23469 published Apr. 27, 2000 discloses fragments of IGFBPs and analogs of IGF-1 for use in, e.g., cancer, ischemic injury, and diabetes treatment.
There exists a continuing need for an effective therapy for the treatment and repair of cartilage, including cartilage damaged as a result of injury and/or disease.